The mortality rate of prostate cancer (PCa) in African American (AA) men is two-folds higher that in Caucasian American (CA) men because they persistently present with a more aggressive form of the disease. However, the genetic risk factors contributing to aggressive PCa in AA men are poorly understood because this area of research has not been sufficiently explored. To address this deficiency, we have enrolled 20 AA families with hereditary PCa in southern Louisiana, including 15 families with aggressive PCa, and we have collected samples from 421 AA individuals with aggressive PCa. We performed exome sequencing on one affected and one unaffected man from a large AA family with aggressive PCa and identified 14 novel non-synonymous variants (ns-variants) that co-segregate with the PCa phenotype in this family. Therefore, we hypothesize that genetic analyses of AA families with aggressive PCa may facilitate the identification of the genetic factors conferring risk to aggressive PCa, and one or more of the 14 identified ns-variants may contribute to aggressive PCa risk in AA men with hereditary or even sporadic PCa. The objective of this study is to identify common germline mutations conferring PCa risk, specifically in AA families and individuals with aggressive PCa, thereby reducing the PCa-related health disparity. In this proposed study, we will: 1) Determine which of the 14 novel ns-variant(s) confers risk to aggressive PCa in AA families. We will genotype the 14 variants in affected and unaffected men to determine which variant(s) co-segregate with PCa in most AA families with aggressive PCa and which variant(s) have the highest frequency in affected individuals. These variants will be validated in an additional 25 AA PCa families provided by Johns Hopkins University. 2) Identify additional variants in the 14 candidate genes conferring risk to aggressive PCa in AA families. We will re-sequence the 14 candidate genes in all of the affected men in the 20 AA families to identify additional variants that may confer risk to aggressive PCa in AA families and AA individuals. 3) Determine the functions of the risk- variant(s) in prostate tumorigenesis. We will perform functional analyses of the risk-variant(s) including RNA and protein expression, cell growth rate, and anchorage-independent colony formation of the cells expressing risk-allele(s) to determine which variant(s) most strongly contributes to aggressive PCa risk in AA. The knowledge gained from this study will advance our understanding of the etiology of aggressive PCa, particularly in the AA population. Results from this proposal may lead to the development of diagnostic tools for early detection and early management of those at an increased risk of developing aggressive PCa to eventually reduce the PCa-related health disparities.